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1.  Thaliporphine Derivative Improves Acute Lung Injury after Traumatic Brain Injury 
BioMed Research International  2015;2015:729831.
Acute lung injury (ALI) occurs frequently in patients with severe traumatic brain injury (TBI) and is associated with a poor clinical outcome. Aquaporins (AQPs), particularly AQP1 and AQP4, maintain water balances between the epithelial and microvascular domains of the lung. Since pulmonary edema (PE) usually occurs in the TBI-induced ALI patients, we investigated the effects of a thaliporphine derivative, TM-1, on the expression of AQPs and histological outcomes in the lung following TBI in rats. TM-1 administered (10 mg/kg, intraperitoneal injection) at 3 or 4 h after TBI significantly reduced the elevated mRNA expression and protein levels of AQP1 and AQP4 and diminished the wet/dry weight ratio, which reflects PE, in the lung at 8 and 24 h after TBI. Postinjury TM-1 administration also improved histopathological changes at 8 and 24 h after TBI. PE was accompanied with tissue pathological changes because a positive correlation between the lung injury score and the wet/dry weight ratio in the same animal was observed. Postinjury administration of TM-1 improved ALI and reduced PE at 8 and 24 h following TBI. The pulmonary-protective effect of TM-1 may be attributed to, at least in part, downregulation of AQP1 and AQP4 expression after TBI.
PMCID: PMC4330958
2.  Collagen-Glycosaminoglycan Matrix Implantation Promotes Angiogenesis following Surgical Brain Trauma 
BioMed Research International  2014;2014:672409.
Surgical brain injury (SBI) is unavoidable during many neurosurgical procedures intrinsically linked to postoperative neurological deficits. We have previously demonstrated that implantation of collagen glycosaminoglycan (CG) following surgical brain injury could significantly promote functional recovery and neurogenesis. In this study we further hypothesized that this scaffold may provide a microenvironment by promoting angiogenesis to favor neurogenesis and subsequent functional recovery. Using the rodent model of surgical brain injury as we previously established, we divided Sprague-Dawley male rats (weighting 300–350 g) into three groups: (1) sham (2) surgical injury with a lesion (L), and (3) L with CG matrix implantation (L + CG). Our results demonstrated that L + CG group showed a statistically significant increase in the density of vascular endothelial cells and blood vessels over time. In addition, tissue concentrations of angiogenic growth factors (such as VEGF, FGF2, and PDGF) significantly increased in L + CG group. These results suggest that implantation of a CG scaffold can promote vascularization accompanied by neurogenesis. This opens prospects for use of CG scaffolds in conditions such as brain injury including trauma and ischemia.
PMCID: PMC4182695  PMID: 25309917
3.  L-Ascorbate Attenuates the Endotoxin-Induced Production of Inflammatory Mediators by Inhibiting MAPK Activation and NF-κB Translocation in Cortical Neurons/Glia Cocultures 
PLoS ONE  2014;9(7):e97276.
In response to acute insults to the central nervous system, such as pathogen invasion or neuronal injuries, glial cells become activated and secrete inflammatory mediators such as nitric oxide (NO), cytokines, and chemokines. This neuroinflammation plays a crucial role in the pathophysiology of chronic neurodegenerative diseases. Endogenous ascorbate levels are significantly decreased among patients with septic encephalopathy. Using the bacterial endotoxin lipopolysaccharide (LPS) to induce neuroinflammation in primary neuron/glia cocultures, we investigated how L-ascorbate (vitamin C; Vit. C) affected neuroinflammation. LPS (100 ng/ml) induced the expression of inducible NO synthase (iNOS) and the production of NO, interleukin (IL)-6, and macrophage inflammatory protein-2 (MIP-2/CXCL2) in a time-dependent manner; however, cotreatment with Vit. C (5 or 10 mM) attenuated the LPS-induced iNOS expression and production of NO, IL-6, and MIP-2 production. The morphological features revealed after immunocytochemical staining confirmed that Vit. C suppressed LPS-induced astrocytic and microglial activation. Because Vit. C can be transported into neurons and glia via the sodium-dependent Vit. C transporter-2, we examined how Vit. C affected LPS-activated intracellular signaling in neuron/glia cocultures. The results indicated the increased activation (caused by phosphorylation) of mitogen-activated protein kinases (MAPKs), such as p38 at 30 min and extracellular signal-regulated kinases (ERKs) at 180 min after LPS treatment. The inhibition of p38 and ERK MAPK suppressed the LPS-induced production of inflammatory mediators. Vit. C also inhibited the LPS-induced activation of p38 and ERK. Combined treatments of Vit. C and the inhibitors of p38 and ERK yielded no additional inhibition compared with using the inhibitors alone, suggesting that Vit. C functions through the same signaling pathway (i.e., MAPK) as these inhibitors. Vit. C also reduced LPS-induced IκB-α degradation and NF-κB translocation. Thus, Vit. C suppressed the LPS-stimulated production of inflammatory mediators in neuron/glia cocultures by inhibiting the MAPK and NF-κB signaling pathways.
PMCID: PMC4077707  PMID: 24983461
4.  Low Dose of Valproate Improves Motor Function after Traumatic Brain Injury 
BioMed Research International  2014;2014:980657.
Background. Traumatic brain injuries (TBIs) are a major health care problem worldwide. Approximately 1.5 million new TBI cases occur annually in the United States, with mortality rates ranging between 35% and 40% in severe patients. Despite the incidence of these injuries and their substantial socioeconomic implications, no specific pharmacological intervention is available for clinical use. Several studies have indicated that 300 mg/kg or 400 mg/kg of valproate (VPA) exhibits neuroprotective effects in animal models. However, humans cannot tolerate high doses of VPA. This study aims to investigate whether 30 mg/kg of VPA administered to rats affects TBIs. Methods. We used a rat model to test the effects of 30 mg/kg of VPA on TBIs. Molecular identifications for histone acetylation and phosphorylation of cAMP response element-binding protein (CREB) and phosphorylated extracellular signal regulated kinase (ERK) were performed. Results. The results indicated that treating adult rats with VPA after TBIs significantly decreased the contusion volume and recovery of contusion-related skilled forelimb reaching deficits. Applying VPA also increased histone acetylation, p-ERK, and p-CREB expression in the brain. Furthermore, applying VPA reduced inflammation, glial fibrillary acidic protein activation, and apoptosis. Conclusion. This study found that 30 mg/kg of VPA assists in treating TBIs in rat models.
PMCID: PMC3933527  PMID: 24689067
5.  Cognitive Impairments Accompanying Rodent Mild Traumatic Brain Injury Involve p53-Dependent Neuronal Cell Death and Are Ameliorated by the Tetrahydrobenzothiazole PFT-α 
PLoS ONE  2013;8(11):e79837.
With parallels to concussive mild traumatic brain injury (mTBI) occurring in humans, anesthetized mice subjected to a single 30 g weight drop mTBI event to the right parietal cortex exhibited significant diffuse neuronal degeneration that was accompanied by delayed impairments in recognition and spatial memory. To elucidate the involvement of reversible p53-dependent apoptosis in this neuronal loss and associated cognitive deficits, mice were subjected to experimental mTBI followed by the systemic administration of the tetrahydrobenzothiazole p53 inactivator, PFT-α, or vehicle. Neuronal loss was quantified immunohistochemically at 72 hr. post-injury by the use of fluoro-Jade B and NeuN within the dentate gyrus on both sides of the brain, and recognition and spatial memory were assessed by novel object recognition and Y-maze paradigms at 7 and 30 days post injury. Systemic administration of a single dose of PFT-α 1 hr. post-injury significantly ameliorated both neuronal cell death and cognitive impairments, which were no different from sham control animals. Cellular studies on human SH-SY5Y cells and rat primary neurons challenged with glutamate excitotoxicity and H2O2 induced oxidative stress, confirmed the ability of PFT-α and a close analog to protect against these TBI associated mechanisms mediating neuronal loss. These studies suggest that p53-dependent apoptotic mechanisms underpin the neuronal and cognitive losses accompanying mTBI, and that these are potentially reversible by p53 inactivation.
PMCID: PMC3842915  PMID: 24312187
6.  Lower circulating preptin levels in male patients with osteoporosis are correlated with bone mineral density and bone formation 
Serum preptin levels among subjects with different bone mineral densities (BMD) were measured and investigated to determine the correlation between BMD and bone-metabolic markers.
Approximately 52 elderly male patients with osteoporosis, 50 elderly men with osteopaenia, and 31 age-matched normal bone mass controls participated in the study. The serum preptin levels and bone metabolic markers were measured by enzyme-linked immunosorbent assay. The relationships between preptin levels, BMD, and metabolic parameters were also assessed.
The serum preptin level was the lowest in the osteoporosis group and positively correlated with BMD. All the bone formation markers in the osteoporosis and osteopaenia groups were significantly reduced compared with those in the normal group. Serum preptin level was positively correlated with all the bone formation markers, whereas no correlation was observed with the bone resorption marker TRACP-5b.
Serum preptin levels are decreased in osteoporosis and osteopaenia patients and positively correlated with BMD. Therefore, preptin is involved in the pathogenesis of osteoporosis, probably through bone formation rather than bone resorption.
PMCID: PMC3570288  PMID: 23363476
Preptin; Osteoporosis; Bone density; Bone metabolic marker
7.  Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation in rats 
Intracerebral hemorrhage (ICH) remains a serious clinical problem lacking effective treatment. Urocortin (UCN), a novel anti-inflammatory neuropeptide, protects injured cardiomyocytes and dopaminergic neurons. Our preliminary studies indicate UCN alleviates ICH-induced brain injury when administered intracerebroventricularly (ICV). The present study examines the therapeutic effect of UCN on ICH-induced neurological deficits and neuroinflammation when administered by the more convenient intraperitoneal (i.p.) route.
ICH was induced in male Sprague-Dawley rats by intrastriatal infusion of bacterial collagenase VII-S or autologous blood. UCN (2.5 or 25 μg/kg) was administered i.p. at 60 minutes post-ICH. Penetration of i.p. administered fluorescently labeled UCN into the striatum was examined by fluorescence microscopy. Neurological deficits were evaluated by modified neurological severity score (mNSS). Brain edema was assessed using the dry/wet method. Blood-brain barrier (BBB) disruption was assessed using the Evans blue assay. Hemorrhagic volume and lesion volume were assessed by Drabkin's method and morphometric assay, respectively. Pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) expression was evaluated by enzyme-linked immunosorbent assay (ELISA). Microglial activation and neuronal loss were evaluated by immunohistochemistry.
Administration of UCN reduced neurological deficits from 1 to 7 days post-ICH. Surprisingly, although a higher dose (25 μg/kg, i.p.) also reduced the functional deficits associated with ICH, it is significantly less effective than the lower dose (2.5 μg/kg, i.p.). Beneficial results with the low dose of UCN included a reduction in neurological deficits from 1 to 7 days post-ICH, as well as a reduction in brain edema, BBB disruption, lesion volume, microglial activation and neuronal loss 3 days post-ICH, and suppression of TNF-α, IL-1β, and IL-6 production 1, 3 and 7 days post-ICH.
Systemic post-ICH treatment with UCN reduces striatal injury and neurological deficits, likely via suppression of microglial activation and inflammatory cytokine production. The low dose of UCN necessary and the clinically amenable peripheral route make UCN a potential candidate for development into a clinical treatment regimen.
PMCID: PMC3271957  PMID: 22257737
anti-neuroinflammation; brain edema; intracerebral hemorrhage; urocortin
8.  Effects of cromolyn sodium on isolated rat's trachea 
Allergy & Rhinology  2011;2(2):e46-e50.
Cromolyn sodium (cromolyn) effectively inhibits both antigen- and exercise-induced asthma when used as an aerosol. Intranasal cromolyn is also recommended for preventing and treating allergic rhinitis. By inhibiting the degranulation of sensitized mast cells, cromolyn reduces the release of mediators that trigger inflammation and the allergic response. The precise pharmacologic activity of cromolyn has not been fully elucidated. This study evaluated the effect of cromolyn on isolated rat's trachea. The following assessments of cromolyn were performed: (1) effect on tracheal resting tension, (2) effect on contraction caused by 10−6 M of methacholine as a parasympathetic mimetic, and (3) effect of the drug on electrically induced tracheal contractions. The results indicated cromolyn could inhibit electrical field stimulation-induced spike contraction when the preparation was increased to 10−4M. Adding cromolyn at doses of ≥10−8 M did not elicit a relaxation or contraction response to 10−6 M of methacholine-induced contraction. It alone had a minimal effect on the basal tension of the trachea as the concentration increased. This study indicates cromolyn had no cholinergic or anticholinergic effect and high concentrations of cromolyn might actually inhibit parasympathetic function of the trachea. Inhibiting parasympathetic function of the trachea through stabilizing the presynaptic nerve by cromolyn may be responsible for protecting patients against antigen- and exercise-induced asthma.
PMCID: PMC3390115  PMID: 22852116
Cromolyn; in vitro study smooth muscle; trachea
9.  Complete Nucleotide Sequence of pCTX-M360, an Intermediate Plasmid between pEL60 and pCTX-M3, from a Multidrug-Resistant Klebsiella pneumoniae Strain Isolated in China ▿ †  
Antimicrobial Agents and Chemotherapy  2009;53(12):5291-5293.
In this work we report the characterization of plasmid pCTX-M360, isolated from a Klebsiella pneumoniae strain from China and encoding the CTX-M-3 extended-spectrum β-lactamase. Sequence analysis of pCTX-M360 revealed extensive similarity with pEL60 and pCTX-M3, two other enterobacterial plasmids of the IncL/M incompatibility group. Compared to pEL60, pCTX-M360 contains several insertions but lacks most of a 27-kb insert found in pCTX-M3, suggesting that it could be an evolutionary intermediate between pEL60 and pCTX-M3.
PMCID: PMC2786365  PMID: 19752275
10.  Tetramethylpyrazine inhibits activities of glioma cells and glutamate neuro-excitotoxicity: Potential therapeutic application for treatment of gliomas 
Neuro-Oncology  2008;10(2):139-152.
We tested the herbal extract 2,3,5,6-tetramethylpyrazine (TMP) for possible therapeutic efficacy against a glioma cell line and against gliomas transplanted into rat brains. In the cultured glioma cells, 50 μM TMP significantly inhibited glutamate-induced increase in intracellular calcium. Significant cell damage (30%) and proliferation suppression (10%), however, occurred only at higher concentrations (200–400 μM). Glioma- neuronal co-culturing resulted in significant neuronal damage and higher proliferation of the glioma cells (140%) compared with single cultures. Low concentrations of TMP (⩽200 μM) attenuated the neuronal damage, suppressed glioma migration, and decreased glioma proliferation in the neuronal-glioma co-culture. Gliomas transplanted into the frontal cortical area exhibited high proliferation, with untreated rats dying 10–23 days later. TMP treatment inhibited tumor growth and significantly extended survival time. The results indicate that TMP can suppress glioma activity, including growth, and protect neurons against glioma-induced excitotoxicity, suggesting that TMP may have therapeutic potential in the treatment of malignant gliomas.
PMCID: PMC2613816  PMID: 18314418
calcium; excitotoxicity; glioblastoma multiforme; tetramethylpyrazine
11.  Higher Expression of Epidermal Growth Factor Receptor Is Associated with Extracellular Matrix Metalloprotease Inducer in Colorectal Adenocarcinoma: Tissue Microarray Analysis of Immunostaining Score with Clinicopathological Parameters 
Disease Markers  2007;22(5-6):309-316.
Aim: Extracellular matrix metalloprotease inducer (EMMPRIN) expression was demonstrated in several cancers, but its expression profile in colorectal cancers remains unclear. Epidermal growth factor receptor (EGFR) was reported to regulate EMMPRIN expression in human epithelial cancers. Our purpose was to determine EMMPRIN expression and its relationship with EGFR in colorectal cancers.
Methods: Immunohistochemical analysis of EMMPRIN and EGFR was performed in tissue microarray slides of 90 surgical specimens including 32 well differentiated, 35 moderately differentiated, and 23 poorly differentiated colorectal adenocarcinomas.
Results: All colorectal adenocarcinomas showed significant immunohistochemical expression of EMMPRIN. The EMMPRIN scores in poorly differentiated (303 ± 21) and moderately differentiated (326 ± 17) colorectal adenocarcinoma were significantly higher than in well differentiated (166 ± 20) colorectal adenocarcinoma. EGFR expression was mainly on the cell surface of tumor cells and the immunostaining scores of EGFR were significantly associated with the advanced clinical T and N stages. A significantly positive relationship between EMMPRIN and EGFR immunostaining scores was also noted.
Conclusions: Increased expression of EMMPRIN and EGFR in colorectal adenocarcinomas is associated with clinicopathological parameters of advanced colorectal adenocarcinoma stages. In addition, the data from this study support the notion that EGFR expression may up-regulate EMMPRIN expression.
PMCID: PMC3851072  PMID: 17264401
Extracellular matrix metalloprotease inducer; EMMPRIN; epidermal growth factor receptor; colorectal; adenocarcinoma

Results 1-11 (11)